DNA sequence analysis has become one of the most important tools in modern biology. Today there is an acute need for new sequencing systems capable of very rapid and inexpensive DNA sequence analysis. We propose to fill that need by commercially developing a novel fluorescence-based, ultra-high-throughput automated DNA sequencer. Our instrument will be based on the first generation prototype already developed by DR. Lloyd Smith and co-workers at the University of Wisconsin, which is currently capable of sequencing 9,300 base pairs per hour (Bio/Technology: Vol. 10 pp. 78-81, 1992). We will work closely with Dr. Smith's lab during this Phases II grant to adapt this design into a second generation commercial prototype with a throughput twenty times greater than current commercially available models. This machine will represent a major break- through in sequencing capability. It will also reduce sequencing cost up to 20-fold compared to currently available sequencing instruments. This instrument will find broad commercial markets beyond the Human Genome Initiative in an ever increasing number of high-throughput research, and emerging human cancer diagnostic and sequencing-based drug discovery applications. PROPOSED COMMERCIAL APPLICATION: This high-throughput instrument will provide the Human Genome Project and sequencing-based cancer diagnostics with an automated DNA sequencer with twenty fold greater throughput than any now on the market by 1996 and significantly reduce the cost of sequencing by reducing the total number of instruments and technicians required to obtain large amounts of finished sequence data, thereby creating new markets in research, diagnostic, and sequence-based drug discovery applications.